A novel series of tetrahydrothieno[2,3-c]pyridin-2-yl derivatives: fluorescence spectroscopy and BSA binding, ADMET properties, molecular docking, and DFT studies

In this study, a series of substituted tetrahydrothieno[2,3-c]pyridin-2-yl (THTP) derivatives, i.e., C1-C3 and N1-N3, was synthesized in one step using 2-amino-5,5,7,7-tetramethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile with two different adjacent chloro- and nitro-substituted groups. Specifically, with a nitrile group on the thiophene structure, six new THTP (C1-C3 and N1-N3)-bearing electron-donating-electron-withdrawing moieties were designed with various pharmacological properties. For the first time in the literature, the synthesis of these target pharmaceutical products was carried out in less steps with high efficiency. Specifically, the notable features of this protocol are its simplicity and high reaction yields. Furthermore, spectroscopic methods were used to verify the structures of all the synthesized compounds (FT-IR, UV, H-1 NMR, and C-13 NMR). Additionally, the binding properties of the molecules with serum albumin were analyzed as a function of concentration and temperature and in the presence of Mg2+, Zn2+, and Ca2+. Moreover, molecular docking calculations were performed against bovine serum albumin, human leukemia inhibitory factor, and DNA. Also, DFT and TD-DFT computational studies were performed at the B3LYP/6-311G** level for structural and spectroscopic confirmation of compounds C1-C3 and N1-N3, and their possible reactivity features were evaluated via FMO "frontier molecular orbital" and NBO "natural bond orbital" analyses. Further, their physicochemical properties such as lipophilicity and water solubility, in addition to ADMET properties were estimated and evaluated. Considering the results obtained from the experiments and computations, it is hoped that this work will be a useful guide for future research on drug design.